The present invention generally relates to implantable medical devices with enhanced patency. More particularly, the present invention relates to ePTFE small caliber vascular grafts that have significantly enhanced patency when coated with polymer bound bio-active agents and methods of applying these agents to such grafts.
It is well known to use bio-active materials to coat structures to be introduced into a living system. Over the last 30 years, research into this area has become increasingly important with the development of various bio-compatible articles for use in contact with blood, such as, for example, vascular grafts, artificial organs, endoscopes, cannulas, and the like.
While various materials have been used to make such articles, synthetic polymers have been increasingly popular as the preferred materials due to their anti-thrombogenic and good mechanical properties. For example, polyurethane is a useful and effective material with a variety of clinical applications. Although synthetic polymers, such as, PTFE and polyurethane, are less thrombogenic than earlier materials, thrombus formation is still a problem.
A thrombus is the formation of a solid body composed of elements of the blood, e.g., platelets, fibrin, red blood cells, and leukocytes. Thrombus formation is caused by blood coagulation and platelet adhesion to, and platelet activation on, foreign substances. When this occurs, a graft is occluded by such thrombogenic material, which in turn, results in decreased patency for the graft. Accordingly, more stringent selection criteria are necessary for small caliber vascular graft materials because the small diameters of these grafts magnify the problem of deposition of such thrombogenic material on the luminal surfaces of the graft. Thus, thrombus formation is a serious complication in surgery and clinical application of small caliber vascular grafts.
Various anti-thrombogenic agents, such as heparin, have been developed and incorporated into bio-compatible articles to combat thrombus formation. In a living system, heparin inhibits the conversion of a pro-enzyme (prothrombin) to its active form (thrombin). Thrombin catalyzes a complicated biochemical cascade which ultimately leads to the formation of a thrombus.
Infection is also a serious concern for articles to be implanted into a host organism. Bacterial, viral and other forms of infection may lead to life-threatening complications when an article is implanted into a host organism. Thus, binding of an anti-infection agent to a surface of an implantable article can reduce the risk of infection when such an article is introduced into a host organism.
The art is replete with various procedures for preventing thrombus formation and/or infection by modifying polymeric surfaces. Various substrate surfaces have previously been described that are suitable for introducing into a biological system. For example, bio-compatible polymer surfaces have been described with various benefits including decreased thrombogenicity, increased abrasion-resistance and improved hydrophilic lubricious properties. Additionally, U.S. Pat. No. 5,061,777 describes procedures for modifying polyurethanes and polyurethaneureas in order to decrease their thrombogenicity. Similarly, U.S. Pat. No. 5,077,352 describes a method of forming a polyurethane complexed with a poly(ethylene oxide) having good adherence to a substrate and good anti-friction properties.
These polymer surfaces, however, are not completely bio-compatible. Thrombus formation and infection continue to pose problems when such articles are implanted within a host. These articles especially are not suitable for use with small caliber vascular grafts where graft patency is critical. Thus, procedures for grafting bio-active agents onto a substrate surface have been developed.
For example, bio-active agents directly bound to the polymer backbone of a polymer coating material are known. Hu et al. in U.S. Pat. No. 5,077,372 disclose a medical device coated with an anti-thrombogenic agent, e.g., heparin, covalently linked to the amino groups of the polyurethane coating. These coating reactions and heparinizations are carried out directly on the device""s surface. Such methods, however, suffer from decreased bio-activity, and consequently, increased thrombogenicity because the bio-active agent, such as, heparin, must be positioned at a distance from the substrate surface in order to optimally interact with its physiological substrates.
Accordingly, alternative methods have been developed for binding bio-active molecules to substrate surfaces. In particular, methods for ionically binding bio-active agents to a substrate via a quarternary ammonium compound have been described. See for example, Mano in U.S. Pat. No. 4,229,838; Williams et al. in U.S. Pat. No. 4,613,517; McGary et al. in U.S. Pat. No. 4,678,660; Solomon et al. in U.S. Pat. No. 4,713,402; and Solomon et al. in U.S. Pat. No. 5,451,424.
These methods, however, are severely limited because the bio-active agent is leached over time from the surface of the substrate. Thus, the protection afforded by the ionically bound bio-active agent is transient at best. Such procedures, therefore, also are not suitable for small caliber grafts.
Accordingly, more permanent methods for binding bio-active molecules to substrate surfaces have also been developed. These methods include covalently binding a bio-active molecule, either directly, or via a spacer molecule, to a substrate surface. For example, photochemical reactions are described which covalently bind bio-active agents to substrate surfaces. See U.S. Pat. Nos. 4,331,697; 4,973,493; 4,979,959; and 5,258,041. When photochemical reactions are used to covalently bind bio-active agents to substrates, however, the choice of substrate is limited. Actinic radiation causes certain substrates, for example PTFE, to degrade. Thus, these methods are limited by the substrate material to be coated.
Even though photochemical reactions are limited to use with certain actinic radiation-resistant substrates, these reactions have been used to indirectly bind bio-active coatings to such substrates via a spacer molecule. For example, several studies describe polyurethane coatings having various spacer molecules that link bio-active agents to polymer substrates. These studies indicate that bio-active agents, such as, for example, heparin, bound to polymer coatings retain more of their bio-activity if they are tethered away from the surface of an article by a spacer.
Thus, Bichon et al. in U.S. Pat. No. 4,987,181 describe a substrate having an adhesive film with anti-thrombogenic properties on its surface. This adhesive film is an olefinic copolymer having carboxylic side chains of the formula Oxe2x95x90CHxe2x80x94NH2xe2x80x94(CH2)nxe2x80x94NH2xe2x80x94CH2xe2x80x94R, wherein R is a heparin molecule or a depolymerization fragment of a heparin molecule. The adhesive film is deposited onto the substrate via photo-initiated polymerization of a suitable monomer. Thus, heparin, or a fragment thereof, is covalently linked to the substrate via an amine spacer.
Although covalent bonding of the bio-active agent to the substrate surface with, or without, a spacer molecule therebetween solves certain problems in the art, these methods continue to be limited. In particular, certain bio-active coatings begin to degrade in response to the photochemical signals used to bind them to the substrate surfaces. In a similar fashion, certain polymeric substrates, such as, polytetrafluoroethylene, degrade when exposed to photochemical reactions and are therefore not useful with such coatings. Thus, attempts have been made to use spacer molecules to bind bio-active agents to substrate surfaces without photochemical reactive groups.
For example, in a four step process, Park et al. disclose immobilizing heparin onto a commercial preparation of a segmented polyetherurethaneurea (PUU) using hydrophilic poly(ethylene oxide) (PEO) spacers of different molecular weights. Their method includes (1) coupling hexamethyldiisocyanate (HMDI) to a segmented polyurethaneurea backbone through an allophanate/biuret reaction between the urethane/urea-nitrogen proton and one of the isocyanate groups on the HMDI. Next, (2) the free isocyanate groups attached to the backbone are then coupled to a terminal hydroxyl group on a PEO to form a PUU-PEO complex. Next (3) the free hydroxyl groups of the PUU-PEO complex are treated with HMDI to introduce a terminal isocyanate group. Finally, (4) the NCO functionalized PUU-PEO is then covalently bonded to reactive functional groups on heparin (xe2x80x94OH and xe2x80x94NH2) producing a PUU-PEO-Hep product. K. D. Park and S. W. Kim, xe2x80x9cPEO-Modified Surfacesxe2x80x94In Vitro, Ex Vivo and In Vivo Blood Compatibilityxe2x80x9d,in Poly(Ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications 283 (J. Milton Harris ed. 1992). This method will be referred to hereinafter as the xe2x80x9cPark Method.xe2x80x9d
Although the use of spacer molecules to tether bio-active molecules to substrate surfaces increases the anti-thrombogenicity of certain substrate surfaces, problems still arise in applying such coatings to chemically inert substrates, such as PTFE, PET and the like. These coatings, which have hydrophilic properties adhere weakly, if at all, to hydrophobic chemically inert substrate surfaces. Thus, the natural repulsive forces between the hydrophilic coatings and the hydrophobic substrate surface serves to decrease the ability of the coating to remain secured to the substrate surface. Thus, plasma treatment of substrate surfaces has been developed as a method to alter the surface properties of such substrates in order to secure coatings thereto.
Accordingly, surfaces of chemically inert tubes have been modified in order to promote binding between a coating and the substrate surface by deposition of a thin layer of an appropriate polymer onto the substrate surface using plasma polymerization (also known as glow discharge) techniques. This technique involves introducing a polymerizable organic monomer in a gaseous state into a vacuum container together with the substrate material to be coated. The gas is then subjected to an electric discharge which initiates a polymerization reaction. This reaction generates ions or free radicals which react with and deposit on the substrate. The polymer formed is normally deposited as a thin layer over the substrate material present in the reaction vessel. Critically, the bulk substrate characteristics are preserved, but the surface properties, which are major determinants of bio-compatibility and non-thrombogenicity, can be modified or improved by plasma polymerization.
Accordingly, Hu et al. in U.S. Pat. No. 4,720,512 describe a method for imparting improved anti-thrombogenic activity to a polymeric support structure by coating it with an amine-rich material, e.g., polyurethaneurea, introducing hydrophobic groups into the amine-rich surface coating through plasma treatment with fluorine compounds, and covalently bonding an anti-thrombogenic agent to the hydrophobic amine-rich surface. Similarly, Hu et al. in U.S. Pat. No. 4,786,556 describe substituting siloxane and silazane compounds during the plasma treatment step of the ""512 patent for the previously disclosed fluorine compounds. See also, Narayanan et al. in U.S. Pat. Nos. 5,132,108 and 5,409,696 and Feijen et al. in U.S. Pat. No. 5,134,192 for other examples of plasma treating substrates prior to introduction of a bio-active molecule.
These preceding methods for plasma treating a substrate surface are limited in their scope because they only work with certain substrates. Thus, they do not provide a general purpose coating composition that can bind to a variety of substrate surfaces.
All of these disclosures have addressed substrate surfaces and/or coatings therefor which can exist within biological systems and, in particular, can increase the anti-thrombogenicity of the surface of, e.g., medical articles. These reactions, however, cannot be universally applied to substrate surfaces. Accordingly, when chemically inert ePTFE vascular grafts are desired to be used, they must be implanted without the benefit of, e.g., an anti-thrombogenic coating, or with one of the previously described coatings. In either case, the patency of the graft is severely compromised because foreign bodies build up on and occlude the graft. This is especially problematic in small caliber grafts where the diameter of the lumen is smaller than other larger diameter vascular grafts. Thus, there is a need for a chemically inert vascular graft material with increased patency and methods of making such a graft. In particular, there is a need for a chemically inert small caliber vascular graft having a surface that adheres well to bio-active coatings applied thereto. The present invention is directed toward providing such a solution.
The present invention relates to implantable medical devices with enhanced patency. In particular, the present invention is directed to an implantable medical device having at least one hydrophobic surface that includes a bio-active coating bound thereto. The bio-active coating contains a polymer backbone bound via an amide or amine chemical bond to one end of a hydrophilic, amine terminated spacer that has at least one amine group at its first and second ends. A bio-active molecule is covalently bound to the unreacted end of the hydrophilic spacer. The hydrophilic spacer is repelled by the hydrophobic surface of the medical device in such a way that the bio-active molecule is extended away from the hydrophobic surface.
In the present invention, the bio-active agent further includes a polymer structure which is defined by a bio-compatible polymeric backbone and at least one pendant moiety of the general formula 
In this formula, R1 is 
R2 is a spacer group selected from the group consisting of oxygenated polyolefins, aliphatic polyesters, polyamino acids, polyamines, hydrophilic polysiloxanes, hydrophilic polysilazanes, hydrophilic acrylates, hydrophilic methacrylates, linear and lightly branched polysaccharides. R3 is a bio-active agent selected from the group consisting of antithrombogenic agents, antibiotic agents, antibacterial agents, antiviral agents, their pharmaceutical salts and mixtures thereof.
In the present invention, any medical device may be used. Preferably the medical device of the present invention is an implantable device such as a vascular graft, endoprosthesis or stent. Other medical devices may also be used, such as, catheters which are minimally invasive. The vascular graft may include a hollow tubular body having an inner and an outer hydrophobic surface. More preferably, the device of the present invention is a small caliber vascular graft and most preferably an ePTFE vascular graft. For purposes of this invention, the term xe2x80x9cvascular graftxe2x80x9d is meant to include endoprostheses which are generally introduce via catheter.
In another embodiment of the present invention, a medical device is provided that includes a bio-active coating over a body fluid contacting surface of the medical device for contacting body fluids. In this embodiment of the invention, the body fluid contacting surface is covalently bonded to the bio-active coating. The bio-active coating includes a polymeric structure defined by a bio-compatible polymeric backbone and at least one pendant moiety of the general formula. 
In this formula, R1 is 
R2 is a spacer group having a chain length of about 9 to about 400 atoms (approximately 100 daltons to 200,000 daltons). Preferably the spacer group has a chain length from about 60 to about 250 atoms. For example, the spacer group may include oxygenated polyolefins, aliphatic polyesters, polyamino acids, polyamines, hydrophilic polysiloxanes, hydrophilic polysilazanes, hydrophilic acrylates, hydrophilic methacrylates, linear and lightly branched polysaccharides. R3 is a bio-active agent selected from the group consisting of antithrombogenic agents, antibiotics agents, antibacterial agents, antiviral agents, their pharmaceutical salts and mixtures thereof.
In yet another embodiment of the invention, there is provided a surface-modified implantable sheet material whose treated surface when exposed to a body fluid is antithrombogenic over extended periods of time. This implantable sheet material includes a hydrophobic substrate material having a plasma induced hydrophilic functionality and a bio-active coating covalently bonded thereto. The sheet can be formed into surgical mesh patches or plugs for tissue and muscle defects, such as, hernias. The bio-active coating has a polymeric structure defined by a bio-compatible polymeric backbone and at least one pendant moiety selected from the group consisting of 
wherein R1 is 
R2 is a spacer group having a chain length of about 9 to about 400 atoms (approximately 100 daltons to about 200,000 daltons). Preferably the spacer group has a chain length from about 60 to about 250 atoms. For example, the spacer group may include oxygenated polyolefins, aliphatic polyesters, polyamino acids, polyamines, hydrophilic polysiloxanes, hydrophilic polysilazanes, hydrophilic acrylates, hydrophilic methacrylates, linear and lightly branched polysaccharides. R3 is a bio-active agent selected from the group consisting of antithrombogenic agents, antibiotics, antibacterial agents, antiviral agents, their pharmaceutical salts and mixtures thereof.
In a further embodiment of the present invention, the medical device having at least one hydrophobic surface has a bio-active coating thereon which is the reaction product of a polymeric backbone, an amine-terminated hydrophilic spacer and a bio-active agent. This product is initiated by a first reaction that includes reacting in the presence of a first dehydrating agent a bio-compatible polymer backbone containing one or more functional groups selected from the group consisting of carboxyl functionality and mixtures thereof with a hydrophilic, amine-terminated spacer having at least one amine group at its first and second ends. In this first reaction, one of the amine groups reacts with one or more functional groups in the polymer backbone to bond the spacer to the polymer backbone. The bio-active coating includes a second reaction in which a bio-active agent is reacted with the remaining unreacted amine terminated end of the spacer in the presence of a second dehydrating agent, which may be the same or different as the first dehydrating agent, to covalently bind the bio-active agent to the spacer.
Application of the bio-active coating is by conventional methods which are known in the art. These methods include, without limitation, dipping, steeping and spraying the article with the bio-active coating. Additional coating and impregnation techniques using pressure to force the coating into the substrate interstices are also contemplated. Multiple layers of the bio-active coating may be applied to the article. Preferably, from about 1 to about 10 layers of the polymer bound bio-active agent are applied to the surface of the article.
In another embodiment of the invention the luminal surface of an article, such as an ePTFE graft, is plasma treated so that hydrophilic groups generated from a gaseous material are introduced onto the surface thereof. Any plasma treatment which is capable of introducing hydrophilic groups onto the surface of an ePTFE vascular graft is useful. It is preferred that a hydrogen-rich plasma be used. Next, the plasma treated surface is contacted with a bio-active coating. The bio-active coating is the reaction product of a first reaction that includes reacting in the presence of a first dehydrating agent a biocompatible polymer backbone containing one or more functional groups selected from the group consisting of carboxyl functionality, unsaturated functionality and mixtures thereof with a hydrophilic amine-terminated spacer having a first end and a second end. The first and second ends of the hydrophilic spacer each have an amine group wherein one of the amine groups reacts with one or more functional groups on the polymer backbone in the presence of a dehydrating agent. This method further includes a second reaction in which a bio-active agent reacts with the remaining unreacted amine-terminated end of the spacer in the presence of a second dehydrating agent to covalently bind the bio-active agent to the spacer.
In this method, the luminal surface of the ePTFE vascular graft includes nodes and fibrils that are resistant to plasma treatment. That is, plasma treatment will not degrade this structure. Conventional plasma treatment, which is known in the art, is useful in this method. For example, the plasma treatment may take place in a plasma ionization chamber with the following parameters: (a) a gas flow rate of about 1 to 500 ml/minute; (b) a chamber pressure of about 0.1 to about 100 torrs; (c) a power setting of about 1 to 700 watts; and (d) a sample exposure time of from about 1 minute to about 24 hours.
In a still further embodiment of the present invention, a method of imparting a bio-active coating to a surface of an article is provided. This method includes plasma treating a surface of the article together with a gaseous material in an ionization chamber so that hydrophilic groups generated from the gaseous material are introduced onto a surface of the article in order to provide a hydrophilic environment thereon. Then, the surface is contacted with a coating composition that includes a polymeric structure defined by a bio-compatible polymeric backbone and at least one pendant moiety selected from the group consisting of 
wherein R1 is 
R2 is a spacer group having from about 9 to about 400 atoms (approximately 100 daltons to about 200,000 daltons) and preferably from about 60 to about 250 atoms. R2 is further selected from the group consisting of oxygenated polyolefins, aliphatic polyesters, polyamino acids, polyamines, hydrophilic polysiloxanes, hydrophilic polysilazanes, hydrophilic acrylates, hydrophilic methacrylates, linear and lightly branched polysaccharides. R3 is a bio-active agent selected from the group consisting of antithrombogenic agents, antibiotics agents, antiviral agents, their pharmaceutical salts and mixtures thereof.
In a further embodiment of the invention, another method of imparting a bio-active coating to a surface of an article is provided. This method includes plasma treating the surface of the article together with a gaseous material in an ionization chamber so that hydrophilic groups generated from the gaseous material are introduced onto the surface of the article in order to provide a hydrophilic environment thereon. Then, the surface is contacted with a polymer bound bio-active composition represented by the structure: 
wherein P is a bio-compatible polymer selected from the group consisting of bio-compatible polymers having carboxyl functionality, unsaturated functionality, and mixtures thereof; R1 is 
R2 is a hydrophilic amine-terminated spacer selected from the group consisting of oxygenated polyolefins, aliphatic polyesters, polyamino acids, polyamines, hydrophilic polysiloxanes, hydrophilic polysilazanes, hydrophilic acrylates, hydrophilic methacrylates, linear and lightly branched polysaccharides; and R3 is a bio-active agent selected from the group consisting of anti-thrombogenic agents, antibiotic agents, antibacterial agents, their pharmaceutical salts, and mixtures thereof.
The bio-active agent useful in the present invention may be chosen from a wide variety of materials. Examples include agents selected from the group consisting of antithrombogenic agents, antibiotic agents, antibacterial agents, antiviral agents, their pharmaceutical salts, and mixtures thereof Furthermore, the bio-active agent is selected from the group consisting of heparin, prostaglandins, urokinase, streptokinase, sulfated polysaccharide, albumin, their pharmaceutical salts and mixtures thereof.